title: MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors.
abstract: microRNA-9-2 and microRNA-9-3 double-mutant mice demonstrate that microRNA-9 (miR-9) controls neural progenitor proliferation and differentiation in the developing telencephalon by regulating the expression of multiple transcription factors. As suggested by our previous study, the Foxg1 expression was elevated, and the production of Cajal-Retzius cells and early-born neurons was suppressed in the miR-9-2/3 double-mutant pallium. At embryonic day 16.5 (E16.5), however, the Foxg1 expression was no longer elevated. The expression of an AU-rich RNA-binding protein Elavl2 increased at E16.5, Elav2 associated with Foxg1 3' untranslated region (UTR), and it countered the Foxg1 suppression by miR-9. Later, progenitor proliferation was reduced in the miR-9-2/3 double-mutant pallium with the decrease in Nr2e1 and Pax6 expression and the increase in Meis2 expression. The analyses suggest that microRNA-9 indirectly inhibits Pax6 expression by suppressing Meis2 expression. In contrast, together with Elavl1 and Msi1, microRNA-9 targets Nr2e1 mRNA 3' UTR to enhance the expression. Concomitantly, cortical layers were reduced, each cortical projection was malformed, and the tangential migration of interneurons into the pallium was impaired in the miR-9-2/3 double mutants. miR-9 also targets Gsh2 3' UTR, and Gsh2, as well as Foxg1, expression was elevated in the miR-9-2/3 double-mutant subpallium. The subpallium progenitor proliferation was enhanced, and the development of basal ganglia including striatum and globus pallidus was suppressed. Pallial/subpallial boundary shifted dorsally, and the ventral pallium was lost. Corridor was malformed, and thalamocortical and corticofugal axons were misrouted in the miR-9-2/3 double mutants.
authors.affiliation: Laboratories for Vertebrate Body Plan and Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN Kobe, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Mikihito
authors.initials: M
authors.lastname: Shibata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aizawa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D011247:Pregnancy; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D013687:Telencephalon / Q000196:embryology / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; C109498:Gsh2 protein, mouse; D018398:Homeodomain Proteins; C551804:MIRN9 microRNA, mouse; D035683:MicroRNAs; C102641:Mrg1 protein, mouse; D009419:Nerve Tissue Proteins; C490258:Nr2e1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors